TY - JOUR
T1 - Genetic characterization of p27kip1and stathmin in controlling cell proliferation in vivo
AU - Berton, Stefania
AU - Pellizzari, Ilenia
AU - Fabris, Linda
AU - D'Andrea, Sara
AU - Segatto, Ilenia
AU - Canzonieri, Vincenzo
AU - Marconi, Daniela
AU - Schiappacassi, Monica
AU - Benevol, Sara
AU - Gattei, Valter
AU - Colombatti, Alfonso
AU - Beletti, Barbara
AU - Baldassarre, Gustavo
N1 - Publisher Copyright:
© Stefania Berton, Ilenia Pellizzari, Linda Fabris, Sara D'Andrea, Ilenia Segatto, Vincenzo Canzonieri, Daniela Marconi, Monica Schiappacassi, Sara Benevol, Valter Gattei, Alfonso Colombatti, Barbara Belletti, and Gustavo Baldassarre.
PY - 2014/10/1
Y1 - 2014/10/1
N2 - The CDK inhibitor p27kip1 is a critical regulator of cell cycle progression, but the mechanisms by which p27kip1controls cell proliferation in vivo are still not fully elucidated. We recently demonstrated that the microtubule destabilizing protein stathmin is a relevant p27kip1 binding partner. To get more insights into the in vivo significance of this interaction, we generated p27kip1 and stathmin double knock-out (DKO) mice. Interestingly, thorough characterization of DKO mice demonstrated that most of the phenotypes of p27kip1 null mice linked to the hyperproliferative behavior, such as the increased body and organ weight, the outgrowth of the retina basal layer and the development of pituitary adenomas, were reverted by co-ablation of stathmin. In vivo analyses showed a reduced proliferation rate in DKO compared to p27kip1 null mice, linked, at molecular level, to decreased kinase activity of CDK4/6, rather than of CDK1 and CDK2. Gene expression profiling of mouse thymuses confirmed the phenotypes observed in vivo, showing that DKO clustered with WT more than with p27 knock-out tissue. Taken together, our results demonstrate that stathmin cooperates with p27kip1 to control the early phase of G1 to S phase transition and that this function may be of particular relevance in the context of tumor progression.
AB - The CDK inhibitor p27kip1 is a critical regulator of cell cycle progression, but the mechanisms by which p27kip1controls cell proliferation in vivo are still not fully elucidated. We recently demonstrated that the microtubule destabilizing protein stathmin is a relevant p27kip1 binding partner. To get more insights into the in vivo significance of this interaction, we generated p27kip1 and stathmin double knock-out (DKO) mice. Interestingly, thorough characterization of DKO mice demonstrated that most of the phenotypes of p27kip1 null mice linked to the hyperproliferative behavior, such as the increased body and organ weight, the outgrowth of the retina basal layer and the development of pituitary adenomas, were reverted by co-ablation of stathmin. In vivo analyses showed a reduced proliferation rate in DKO compared to p27kip1 null mice, linked, at molecular level, to decreased kinase activity of CDK4/6, rather than of CDK1 and CDK2. Gene expression profiling of mouse thymuses confirmed the phenotypes observed in vivo, showing that DKO clustered with WT more than with p27 knock-out tissue. Taken together, our results demonstrate that stathmin cooperates with p27kip1 to control the early phase of G1 to S phase transition and that this function may be of particular relevance in the context of tumor progression.
KW - Cell cycle
KW - Gene knock-out
KW - P27
KW - Proliferation
KW - Signaling pathway
KW - Stathmin
UR - http://www.scopus.com/inward/record.url?scp=84926670118&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84926670118&partnerID=8YFLogxK
U2 - 10.4161/15384101.2014.949512
DO - 10.4161/15384101.2014.949512
M3 - Article
C2 - 25486569
AN - SCOPUS:84926670118
SN - 1538-4101
VL - 13
SP - 3100
EP - 3111
JO - Cell Cycle
JF - Cell Cycle
IS - 19
ER -